This Project is composed of four interrelated studies on the neurobiology of prepubertal major depressive illness: 1) Neurobiological Markers and Mechanisms in Pepubertal Children with Major Depressive Illness Stability Over Time; 2) Neurobiology of Suicidal Behavior in Affective and Nonaffective Prepubertal Children; 3) Red Cell Membrane Defects in Prepubertal Depressive Illness; and 4) High Risk Study: Trait Markers for Early Onset Affective Illness. These will be supported by seven different core facilities, with funding requested for only three. The main objectives are: (1) to determine: a) if markers found in the euthymic state in prepubertal major depressive children (shortened REM latency, increased sleep GH secretion, deceased GH response to ITT) and in adult bipolars (RBC membrane hydrocarbon defects) are stable over long term recovery; b) if they change with recurrences of dysthymia, major depression or bipolar disorder. (2) To determine: a) if they are true trait markers by ascertaining if they are present significantly more ofen in as yet unaffected, normal pepubertal children from families with very high morbidity risk for affective illness, compared to normal children from families with negative familial history for affective illness; and b) if the presence of such markers predicts the development of affective illness during follow-up in the high risk children. (3) To test the roles of three different neurotransmitter systems (cholinergic, noradrenegic and serotonergic) in the regulation of these markers by carrying out day and night tests including baseline measures (including urinary 6-OH melatonin) and provocative challenges including physostigmine, clonidine, orthostatic challenge, and 5-hydroxytryptophan. Data about the site of neuroregulatory disturbances will be gathered by synthetic CRF and GRF challenges. (4) To determine to which exent the neurobiology of suicidal planning and behavior converges, diverges, or interact with that of affective illness in prepuberty. (5) In addition, these studies will provide much needed normative data on the neuroregulation of EEG sleep and neuroendocrine function before puberty, and also, during follow-up, on the possible effects of puberty. To accomplish these aims, patient samples and two samples of normal children, all prebubertal, will be studied at baseline: 1) children with major depression, 2) children with nonaffective, nonsuicidal psychiatric disorders, 3) children with suicidal nonaffective psychiatic disorders, 4) normal children at very high risk for affective illness and 5)\normal children at very low risk for affective illness. All samples will be followed for up to 5 years and restudied at pre-specified points in time. The resarch program has the potential to significantly advance our understanding of familial transmission, risk factors, course and neurobiology of early onset affective illness and suicidal behavior, and can form the basis of significant diagnostic, prognostic, and prophylactic advances in this important area of child psychopathology.